Our goal is to determine the mechanism of abnormal brain function in severe liver disease. Particular attention will be devoted toward establishing unequivocally whether ammonia is a primary toxin to the central nervous system and whether a direct relationship exists between abnormal cerebral ammonia metabolism and hepatic encephalopathy. Toward these ends, we have several approaches: (1) to examine the uptake and metabolism of 13NH3 entering brain from blood in normal individuals and patients with liver disease; (2) to determine the metabolic fate and rate of turnover of 13NH3 in the brains of normal rats and of animals made chronically hyperammonemic by a portacaval shunt; (3) to assess the effect of ammonia intoxication on intracellular transport of reducing equivalents via the malate-aspartate shuttle system; and (4) to assess whether animals made chronically hyperammonemic are more susceptible to acute hypoxic ischemia insults than are normal animals. The findings should provide new insights into the degree to which cerebral ammonia metabolism is altered in conditions of chronic hyperammonemia in man; they may also offer clues as to the biochemical mechanisms of ammonia intoxication and the reasons why patients with chronic liver disease appear to be more susceptible to a variety of superimposed metabolic insults. Because hyperammonemia is generally believed to be a major pathogenic factor in human hepatic encephalopathy, a clarification of the role of abnormal ammonia metabolism in patients with this condition may suggest more effective lines of therapy.